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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
1
Jean-YvesMaillardCardiffSchoolofPharmacyandPharmaceuticalSciencesCardiffUniversity
ChlorhexidineUseandBacterialResistance
HostedbyDr. LynneSehulster
www.webbertraining.com September27,2018
Background
Bacterialresponsestobiocides
Bacterialresistancetochlorhexidineinsitu
Bacterialresistancetochlorhexidineinvitro
Realitycheck
Conclusions
OVERVIEW
J-Y Maillard – Teleclass, 2018
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
2
BACKGROUND
J-Y Maillard – Teleclass, 2018
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DISINFECTIONSurfaceLiquid
Materials (wipes)
ANTISEPSISAntimicrobial gel/liquid
dressings
PRESERVATIONWood Plastictextiles
DOMESTIC PRODUCTSWashing liquid
Washing up liquidChopping board
‘ANTIMICROBIAL’SURFACESEnvironmental
Medical (Implant)
FoodPharmaceutical
PRESERVATION
BACKGROUND: context - biocide usage
J-Y Maillard – Teleclass, 2018
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
3
Organism Persistence
Acinetobacter spp. 3 days to 5 months
Clostridium difficile (spores) 5 months
Enterococcus spp. includingvancomycin-resistant enterococci
5 days to 4 months
Escherichia coli 1.5 h to 16 months
Klebsiella spp. 2 h to>30 months
Mycobacterium tuberculosis 1 day to 4 months
Pseudomonas aeruginosa 6 h to 16 months
Salmonella typhimurium 10 days to 4.2 years
Shigella spp. 2 days to 5 months
Staphylococcus aureus, including MRSA 7 days to 7 months
Haemophilus influenzae 12 days
BACKGROUND: persistence
J-Y Maillard – Teleclass, 2018
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CONTAMINATED SURFACES
PATIENTS
HEALTHCARE WORKERS
PATIENTS
SURFACE DISINFECTION- liquid disinfectants- antimicrobial pre-wetted wipes- UV irradiation- gas
ANTIMICROBIAL SURFACES
Ø Hand hygiene compliance: 30-85%
Ø Surface disinfection: 32%
BACKGROUND: interventions
J-Y Maillard – Teleclass, 2018
HAND HYGIENE- liquid- Gel/rub- Wipes
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
4
O’Neill. 2016. Tackling drug-resistant infections globally: Final report and recommendations. The Review Antimicrobial resistance. HM Government.
Deaths per annum worldwide
BACKGROUND: end of antibiotic era?
J-Y Maillard – Teleclass, 2018
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Peer-reviewed articles / reviews since 1998Title and abstract: chlorhexidine + resistance
0
20
40
60
80
100
120
Web of ScienceGoogle ScholarPubMed
J-Y Maillard – Teleclass, 2018
BACKGROUND: CHX RESISTANCE
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
5
BACTERIAL RESPONSES TO BIOCIDES
J-Y Maillard – Teleclass, 2018
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- prions
- bacterial spores
- protozoal oocysts
- mycobacteria- naked viruses
- protozoal cysts
- vegetative Gram- negative
- fungi
- protozoa
- vegetative Gram-positive
- enveloped viruses
Resistance to Biocides
Exceptions
Exceptions
Exceptions
Exceptions
BACTERIAL RESPONSES TO BIOCIDESIntrinsic resistance
J-Y Maillard – Teleclass, 2018
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
6
DEGREE OF DAMAGE AND AUTOCIDAL ACTIVITY CONSEQUENCES
Ø Disruption of the transmembrane PMF leading to an
uncoupling of oxidative phosphorylation and inhibition of
active transport across the membrane
Ø Inhibition of respiration or catabolic/anabolic reactions
Short exposure Reversible eventsØ Disruption of metabolic processes Prolonged biocidal
exposureØ Disruption of replication
Ø Loss of membrane integrity resulting in leakage of essential
intracellular constituents (K+, inorganic phosphate, pentoses,
nucleotides and nucleosides, proteins)
Imbalance of pHi
Irreversible eventsØ Coagulation of intracellular materials Autocidal (commitment
to a cell death pathway)
Ø LYSIS Cell death
BACTERIAL RESPONSES TO BIOCIDESBacteria – biocide interactions
J-Y Maillard – Teleclass, 2018
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DEGREE OF DAMAGE AND AUTOCIDAL ACTIVITY CONSEQUENCES
Ø Disruption of the transmembrane PMF leading to an
uncoupling of oxidative phosphorylation and inhibition of
active transport across the membrane
Ø Inhibition of respiration or catabolic/anabolic reactions
Short exposure Reversible eventsØ Disruption of metabolic processes Prolonged biocidal
exposureØ Disruption of replication
Ø Loss of membrane integrity resulting in leakage of essential
intracellular constituents (K+, inorganic phosphate, pentoses,
nucleotides and nucleosides, proteins)
Imbalance of pHi
Irreversible eventsØ Coagulation of intracellular materials Autocidal (commitment
to a cell death pathway)
Ø LYSIS Cell death
BACTERIAL RESPONSES TO BIOCIDESBacteria – biocide interactions
J-Y Maillard – Teleclass, 2018
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
7
EXPRESSION OF SPECIFIC
MECHANISMS
PHYSIOLOGICAL CHANGES
BIOFILMChange in lag phase/
growthrate
Change in metabolic pathwayin
activ
atio
n
reduction in accumulation
reduction in uptake and penetration
CO-R
ESIS
TANC
E
CROSS-RESISTANCE RESISTANCE
REPAIR
Enhance DNA
repair ability
BACTERIAL RESPONSES TO BIOCIDES
J-Y Maillard – Teleclass, 2018
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EXPRESSION OF SPECIFIC
MECHANISMS
PHYSIOLOGICAL CHANGES
BIOFILMChange in lag phase/
growthrate
Change in metabolic pathwayin
activ
atio
n
reduction in accumulation
reduction in uptake and penetration
CO-R
ESIS
TANC
E
CROSS-RESISTANCE RESISTANCE
REPAIR
Enhance DNA
repair ability
BACTERIAL RESPONSES TO BIOCIDES
J-Y Maillard – Teleclass, 2018Acquisition of genetic determinants
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
8
OMP profile LPS profile
• Pseudomonas stutzeri with decreased MIC to chlorhexidine and CPC• Cross-resistance to polymyxin and gentamicin
Change in LPS, reduction of porins
REDUCTION IN PENETRATION
BACTERIAL RESPONSES TO BIOCIDESChanges in membrane properties
J-Y Maillard – Teleclass, 2018
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Fig 1
Copyright © 2006 Nature Publishing GroupNature Reviews | Microbiology
Numerous drugs
H+
ATP ABC superfamily
MFS superfamily
MATE family
SMR family
RND family
ADP + Pi
Numerous drugs
Periplasm
Inner membrane
Outer membrane
H+
H+
H+(Na+)
QacC
QacA
LmrA
NorM
Acriflavine BenzalkoniumCetrimideChlorhexidinePentamidine
AminoglycosidesFluoroquinolonesCationic drugs
Acriflavine BenzalkoniumCetrimide
AcrBAcrA
AcrA
Cytoplasm
TolC
Piddock 16/06/06
BACTERIAL RESPONSES TO BIOCIDESReduction in antimicrobial accumulation
J-Y Maillard – Teleclass, 2018
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
9
GENERAL STRESS RESPONSE
SOS RESPONSEMUTATIONS
GLOBAL RESPONSE
STRESS
BIOCIDE
NARROW RESPONSE
SELECTIVE PRESSURE
REPAIREFFLUX MEMBRANE CHANGES METABOLISM
Adaptive mutations
BACTERIAL RESPONSES TO BIOCIDESStress response and selective pressure
J-Y Maillard – Teleclass, 2018
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ALCOHOLS
CHLORHEXIDINE
BENZALKONIUM CHLORIDE
QACs
GLUTARALDEHYDE
PHENOLICS
POVIDONE IODINE
Ø Reports of bacterial resistance from 1958!
BACTERIAL RESPONSES TO BIOCIDES
J-Y Maillard – Teleclass, 2018
OXIDISING AGENTS
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
10
• Resistance: surviving exposure to a biocide concentration that will kill the rest of the population
Russell. Lancet Infect Dis 2003; 3: 794-803
• Resistance in practice: Bacterial survival following biocide challenge at “in use”/ ”during use” concentration.
Maillard & Denyer. Chem Oggi 2009; 27: 26-8.Maillard et al. Micro Drug Resist 2013; 19:344-54.
Wesgate et al. AJIC 2016, 44, 458-464.
• Reduced susceptibility: increase in MBC comparing to the initial population or a reference strain
- For data based on MIC changes: increase in MIC
• Tolerance: inhibited but not killed- survival in a product (preservative system)
• Cross-resistance: Bacterial survival following biocide challenge at “in use”/ ”during use” concentration AND to unrelated antimicrobials; may include emerging clinical resistance to chemotherapeutic antibiotics
BACTERIAL RESPONSES TO BIOCIDES
J-Y Maillard – Teleclass, 2018
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• SCENIHR 2009: Assessment of the Antibiotic Resistance Effects of Biocides.
http://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_021.pdf
• SCENIHR 2010: Research strategy to address the knowledge gaps on the antimicrobial resistance effects of biocides.
http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_028.pdf
• SCCS 2011: Opinion on Triclosan Antimicrobial Resistance.
http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_023.pdf
• SCENIHR 2014: Nanosilver: safety, health and environmental effects and role in antimicrobial resistance. http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_039.pdf
European Commission Opinions
SCCP/1251/09
Scientific Committee on Consumer Safety
SCCS
Opinion on triclosan
Antimicrobial Resistance
The SCCS approved this opinion at its 7th plenary of 22 June 2010 after public consultation
1
Scientific Committee on Emerging and Newly Identified Health Risks
SCENIHR
Assessment of the Antibiotic Resistance Effects of Biocides
The SCENIHR adopted this opinion at the 28th plenary on 19 January 2009 after public consultation.
J-Y Maillard – Teleclass, 2018
BACTERIAL RESPONSES TO BIOCIDESRegulators
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
11
Biocide Products Regulation … and resistance (effective since 1/09/2013)
1-b(ii) …the biocidal product has no unacceptable effects on the target organisms, in particular unacceptable resistance or cross-resistance
3-b …the chemical diversity of the active substances is adequate to minimise the occurrence of resistance in the target harmful organism.
Effects on target organisms
75. Where the development of resistance or cross-resistance to the active substance in the biocidal product is likely, the evaluating body shall consider actions to minimise the consequences of this resistance. This may involve modification of the conditions under which an authorisation is given. However, where the development of resistance or cross-resistance cannot be reduced sufficiently, the evaluating authority shall conclude that the biocidal product does not satisfy criterion (ii) under point (b) of Article 19(1).
BACTERIAL RESPONSES TO BIOCIDESRegulators
J-Y Maillard – Teleclass, 2018
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U.S. Food and Drug Administration (Press release 2nd September 2016)
The agency issued a proposed rule in 2013 after some data suggested that long-term exposure to certain active ingredients used in antibacterial products — for example, triclosan (liquid soaps) and triclocarban (bar soaps) — could pose health risks, such as bacterial resistance…This included data from clinical studies demonstrating that these products were superior to non-antibacterial washes in preventing human illness or reducing infection
“…some data suggest that long-term exposure to certain active ingredients used in antibacterial products—for example, triclosan (liquid soaps) and triclocarban (bar soaps)—could pose health risks, such as bacterial resistance …”
FDA issues final rule on safety and effectiveness of antibacterial soaps
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm517478.htm (accessed 19/09/2018)
BACTERIAL RESPONSES TO BIOCIDESRegulators
J-Y Maillard – Teleclass, 2018
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
12
BACTERIAL RESISTANCE TO CHLORHEXIDINE IN SITU
J-Y Maillard – Teleclass, 2018
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SKIN PREPARATIONS• Skin care 2%• Hand hygiene ± alcohol
• Patient preoperative scrub and showers (combined with alcohol)• Vascular access site dressings (chlorhexidine sponge dressing and a chlorhexidine
gel pad)Ø Vascular access - such as central venous catheters, skin preparation
solutions and insertion site dressings are recommended as interventions that may prevent Central Line-Associated Bloodstream Infections (CLABSIs)
Ø Vascular access cathetersØ Peripherally Inserted Central venous catheter
DEVICES• Central Venous catheter – CHX impregnated catheters (intraluminally and
extraluminally)• Needleless IV connectors (combined chlorhexidine and silver)
SOLUTIONS• Oral care mouthwash• Urology – bladder irrigation 0.005%
BACTERIAL RESISTANCE TO CHX IN SITUCHX applications
J-Y Maillard – Teleclass, 2018
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ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
13
Products Concent-ration
Additional biocides
Uses
Topical medicines (gel or liquid)
7.1% None Umbilical cord care to prevent cord infection and/or sepsis and reduce neonatal mortality.
Topical solution(liquid, cloth, sponge applicators, swab sticks)
2% , 3.15%, 4%, or 5%
Isopropyl alcohol Skin preparation for surgery, invasive procedures, central lines to prevent hospital- acquired infections
Scrub solution (liquid detergent)
2% or 4% Isopropyl alcohol • Preoperative bathing, general skin cleansing to prevent hospital-acquired infection
• Preoperative hand scrub and hand disinfection to prevent the spread of microorganisms
Irrigation solution 0.015% or 0.05%
Cetrimide Irrigation of wounds to prevent infection
Topical cream 0.1% Cetostearyl alcohol Cetrimide
Wound cleaning (over-the-counter first-aid cream) to prevent infection
Washcloth 2% none Daily bathing in intensive care unit (ICU) patients to prevent hospital-acquired infection
Gauze dressing 0.5% - Wound or burn dressing to prevent infection
Catheter dressing 2% None Catheter dressings to prevent hospital- (gel pad, foam disk, semi-acquired infection permeable transparent dressing)
Hand rub (gel) 0.5% or 1% Ethanol Hand sanitizing to prevent the spread of microorganisms
Dental solution 0.12% or 0.2%
Ethanol • Decontaminate oral cavity to prevent (oral rinse or spray)• Periodontal disease and mucositis treatment
Concentrated stock solution
20% None Preparation of dilutions for skin cleansing and general disinfection
https://www.healthynewbornnetwork.org/hnn-content/uploads/CWG-Chlorhexidine-Applications-English_October_2015.pdf(accessed 19-09-2018)
BACTERIAL RESISTANCE TO CHX IN SITUCHX applications
J-Y Maillard – Teleclass, 2018
Products Concent-ration
Additional biocides
Uses
Topical medicines (gel or liquid)
7.1% None Umbilical cord care to prevent cord infection and/or sepsis and reduce neonatal mortality.
Topical solution(liquid, cloth, sponge applicators, swab sticks)
2% , 3.15%, 4%, or 5%
Isopropyl alcohol Skin preparation for surgery, invasive procedures, central lines to prevent hospital- acquired infections
Scrub solution (liquid detergent)
2% or 4% Isopropyl alcohol • Preoperative bathing, general skin cleansing to prevent hospital-acquired infection
• Preoperative hand scrub and hand disinfection to prevent the spread of microorganisms
Irrigation solution 0.015% or 0.05%
Cetrimide Irrigation of wounds to prevent infection
Topical cream 0.1% Cetostearyl alcohol Cetrimide
Wound cleaning (over-the-counter first-aid cream) to prevent infection
Washcloth 2% none Daily bathing in intensive care unit (ICU) patients to prevent hospital-acquired infection
Gauze dressing 0.5% - Wound or burn dressing to prevent infection
Catheter dressing 2% None Catheter dressings to prevent hospital- (gel pad, foam disk, semi-acquired infection permeable transparent dressing)
Hand rub (gel) 0.5% or 1% Ethanol Hand sanitizing to prevent the spread of microorganisms
Dental solution 0.12% or 0.2%
Ethanol • Decontaminate oral cavity to prevent (oral rinse or spray)• Periodontal disease and mucositis treatment
Concentrated stock solution
20% None Preparation of dilutions for skin cleansing and general disinfection
https://www.healthynewbornnetwork.org/hnn-content/uploads/CWG-Chlorhexidine-Applications-English_October_2015.pdf(accessed 19-09-2018)
BACTERIAL RESISTANCE TO CHX IN SITUCHX applications
J-Y Maillard – Teleclass, 2018
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
14
Contaminant(s) Site(s) of microbes Mechanism of contamination/sourcePseudomonas spp. Not stated Refilling contaminated bottles; washing used bottles using cold tap
water; contaminated washing apparatus; low concentration (0.05%)
Pseudomonas sp., Serratia
marcescens,
Flavobacterium sp.
Not stated Not determined, but authors speculate due to over-dilution or refilling
of contaminated bottles
Pseudomonas aeruginosa Wounds Tap water used to dilute stock solutions; low concentration (0.05%)
Bulkholderia cepacia Blood, wounds, urine,
mouth, vagina
Metal pipe and rubber tubing in pharmacy through which deionized
water passed during dilution of chlorhexidine; low concentration
Ralstonia pickettii Blood Contaminated bidistilled water used to dilute chlorhexidine; low
concentration (0.05%)
Ralstonia pickettii Blood (pseudo-
bacteremia)
Distilled water used to dilute chlorhexidine; low concentration
(0.05%)
Serratia marcescens Bood, urine, wounds,
sputum, others
Not determined, but use of nonsterile water for dilution to 2% and
distribution in reusable nonsterile containers
Ralstonia pickettii Blood
(pseudobacteremia)
Distilled water used to dilute chlorhexidine; low concentration
(0.05%)
Bulkholderia cepacia Blood Intrinsic contamination, Contaminated 0.5% chlorhexidine
Serratia marcescens Blood Intrinsic contamination, 2% aqueous chlorhexidine antiseptic
Maillard J-Y. Bacterial Resistance to biocides In Block’s Disinfection, Sterilization & Preservation. submitted
BACTERIAL RESISTANCE TO CHX IN SITUCHX contaminated products and infections
J-Y Maillard – Teleclass, 2018
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Antiseptic Contaminants Mechanisms of contamination/sourceAlcohols B. cereus, B. cepacia Intrinsic contamination, contaminated tap
waterChlorhexidine Pseudomonas spp.,
B. cepacia, Flavobacetriumspp., Ralsonia pickettii, Achromobacterxylosoxidans, S. marcescens
Refilling contaminated bottle, contaminated washing apparatus(0,05%),Topping up stock solution (1:1000-1:5000), metal pipe (low concentration), contaminated water (0.05%), atomizer (0.06%)
Chlorhexidine+ cetrimide
Ps. multivorans, St. maltophilia
Tap water (0.05% CHX & 0.5%cetrimide), contaminated deionized water
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN SITUCHX contaminated products and infections
28
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
15
BACTERIAL RESISTANCE TO CHLORHEXIDINE IN
VITRO
J-Y Maillard – Teleclass, 2018
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MICs of Ps aeruginosa cultures following repeated exposure to CHX ( 5 µg/mL)
Culturenumber
Original MIC (µg/mL) before multiple
exposure to CHX (5 µg/mL)
MIC (µg/mL CHX) after 5
subcultures in CHX (µg/mL)
1a 8-10 >70c
2 28b >70c
3 >40b >70c
4 >50b >70c
5 70b >70c
a: standard parent strainb: cultures from step-wise training methodc: these cultures were found stable after 15 subcultures in CHX-free broth
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITROArtificial decrease in CHX susceptibility
30
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
16
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITRODecreased susceptibility following short CHX exposure
Mean MBC (%)
Biocide Baseline 0.0004 % CHG
0.0001 % CHG
0.00005 % CHG
0.0004 % BZC
0.0001 % BZC
0.00005 % BZC
CHG 0.01 0.20 ± 0.00 0.20 ± 0.09 0.04 ± 0.00 0.30 ± 0.00 0.20 ± 0.00 0.20 ± 0.10
BZC 0.003 0.20 ± 0.00 0.05 ± 0.02 0.20 ± 0.20 0.80 ± 0.00 0.20 ± 0.00 0.30 ± 0.20
Salmonella enterica 1344 susceptibility following a 5 min exposure to CHG or BZC
GREEN = increased MBC by 10-50 foldsRED = >50 folds
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J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITRODecreased susceptibility following short CHX exposure
Mean MBC (%)
Biocide Baseline 0.0004 % CHG
0.0001 % CHG
0.00005 % CHG
0.0004 % BZC
0.0001 % BZC
0.00005 % BZC
CHG 0.01 0.20 ± 0.00 0.20 ± 0.09 0.04 ± 0.00 0.30 ± 0.00 0.20 ± 0.00 0.20 ± 0.10
BZC 0.003 0.20 ± 0.00 0.05 ± 0.02 0.20 ± 0.20 0.80 ± 0.00 0.20 ± 0.00 0.30 ± 0.20
Salmonella enterica 1344 susceptibility following a 5 min exposure to CHG or BZC
GREEN = increased MBC by 10-50 foldsRED = >50 folds
Baseline MIC
CHG MIC 1
CHG MIC 2
CHG MIC 3
CHG MIC 4
Baseline MBC
CHG MBC 1
CHG MBC 2
CHG MBC 3
CHG MBC 4
1344 0.003 0.08 0.06 0.06 0.067 0.01 0.20 0.10 0.10 0.15
14028S 0.003 0.01 0.02 0.03 0.01 0.006 0.10 0.09 0.09 0.2
CHG exposure: 0.0004 % for S. enterica 1344 and 0.0001 % for S. enterica 14028S
Reproducibility
32
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
17
Burkholderia lata 383 Number of passages
Baseline susceptibility5 min CHG exp
without CHG With CHG 0.004%
1 5 10 1 5 10
CHG MBC (%) 0.01 0.5 0.008 0.009 0.006 0.15 0.1 0.01
BZC MBC (%) 0.003 0.15 0.004 0.006 0.006 0.019 0.05 0.006
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITRODecreased susceptibility following short CHX exposure
2013
33
Burkholderia lata 383 Number of passages
Baseline susceptibility5 min CHG exp
without CHG With CHG 0.004%
1 5 10 1 5 10
CHG MBC (%) 0.01 0.5 0.008 0.009 0.006 0.15 0.1 0.01
BZC MBC (%) 0.003 0.15 0.004 0.006 0.006 0.019 0.05 0.006
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITRODecreased susceptibility following short CHX exposure
2013
Salmonella enterica 14028S Number of passages
Baseline susceptibility5 min CHG exp
without CHG With CHG 0.004%
1 5 10 1 5 10
CHG MBC (%) 0.006 0.5 0.001 0.006 0.009 0.08 0.08 0.006
BZC MBC (%) 0.008 0.3 0.006 0.007 0.006 0.019 0.02 0.008
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
18
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITROCross-resistance between CHX and antibiotics
35
London: 19
South-East: 3South-West: 2
Eastern England: 8
Wales: 0
West Midlands: 8
East Midlands: 3
Yorkshire and Humberside: 5
North-West: 15
North-East: 1
Scotland: 4
Northern Ireland: 1
Ø 160 K. pneumoniaeØ 50 E. coli
Ø 69 hospitalsØ July 2010 to August 2015
Ø Rectal swabs, urine samples, faeces, blood cultures
CHX BZC CS SNMIC MBC MIC MBC MIC MBC MIC MBC
CHX MICMBC
BZC MICMBC
CS MICMBC
SN MICMBC
Carb
apen
ems*
Ceph
alos
pori
ns
Am
ikac
in
Azt
reon
am
Cpir
oflo
xaci
n
Tige
cycl
ine
Min
ocyc
line
Colis
tin
CHX MIC
MBC
BZC MIC
MBC
CS MIC
MBC
SN MIC
MBC
Spearman's r scoresPositive correlation Inverted correlation
Strong +0.7 to +0.9 -0.7 to -0.9Moderate +0.4 to +0.6 -0.4 to -0.6Weak +0.1 to +0.3 -0.1 to -0.3
no statistically significant correlation
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITROCHX and carbapenem resistance
36
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
19
BacteriaSource of isolates
Biocide exposure
Resistance to unrelated biocides
Resistance to antibiotics
Mechanisms
Burkholderia lata CHG (0.005%) BZC (0.005%)
No significant change in MIC or MBC to CHG or BZC
Decrease in susceptibility to CAZ, CIP, IMP
Upregulation of outermembrane protein and ABC transporter
S. aureus TRI (0.0004%) Increase in MIC and MBC to TRI
Resistance to CIP, AMP
ND
E. coli CHG (0.0004%) No change in MIC or MBC to CHG
Resistance to TOB, TIC, AMP
ND
S. aureus H2O2 (0.001%) No change in MIC or MBC to H2O2
Resistance to CIP, AMP
ND
Clinical isolates of S. aureus
In situ High MIC to CHG Resistance CEF, RIF, TSX, CHL
Efflux: qacAB
Acinetobacter baumannii
CHG (4%) Increased MIC to CHG
Resistance to CIP, IMP, MEM, GEN, TOB, NEL, TET, DOX
Efflux: increased expression in adeb, abeS, amvAPorins: decreased expression in ompA
Acinetobacter baumannii
BZC (0.1%) Increased MIC to BZC
Resistance to CIP, GEN, NEL, TET, DOX,
Efflux: increased expression in adeb,abeSPorins: decreased expression in ompA, carO
Maillard J-Y. Bacterial Resistance to biocides In Block’s Disinfection, Sterilization &Preservation. submitted
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITROCross-resistance between CHX and antibiotics
37
• Genotypic, transcriptomic proteomic and phenotypic of Salmonella enterica serovarTyphimurium tolerant to chlorhexidine.
• Alteration of antibiotic susceptibility with clinical significance following exposure to CHX 1 μg/mL for 30 min (mid log phase culture)
• Implication of a defence network including multiple cellular targets associated with membrane synthesis, SOS response, virulence and metabolism
ST24WT CHX MIC: 1.96 μg/mLST24CHX CHX MIC: >50 μg/mL
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITROGenetic basis for resistance – multiple mechanisms
38
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
20
Efflux gene(% carriage in isolate)
Bacteria(number of isolates)
Resistant to
qacA/B (83.0%)smr (77.4%)norA (49.0%)norB (28.8%)
High-level mupirocin-resistant-meticillin-resistant S. aureus
(MRSA) (53)
Chlorhexidine
qacA/B (80%) Staphylococcus epidermidis (25) Chlorhexidine
sepA (95.3%)mepA (89.4%)norA (86.4%)lmrS (60.8%)qacAB (40.5%)smr (3.7%).
MRSA (82), methicillin –sensitive S. aureus (MSSA) (219)
Chlorhexidine
qacA/B (83%) smr (1.6%) MRSA (60) Benzalkonium chlorideBenzethonium chlorideChlorhexidine
qacA (26% for HMRSA, 67% for VISA)
qacC (5% for HMRSA, 4%MSSA, 17%VISA)
Hospital-acquired (HA)-MRSA (38), 25 Community-acquired (CA)-MRSA (25)
Vancomycin insensitive S. aureus (VISA) (6) ; MSSA (25)
QACChlorhexidine
Maillard J-Y. Bacterial Resistance to biocides In Block’s Disinfection, Sterilization &Preservation. submitted
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITROCarriage of efflux pump genes in healthcare setting isolates
39
53 high-level mupirocin resistant MRSA
Ø 83% CHX MIC > 4 µg/mL
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITROCarriage of efflux pump genes in healthcare setting isolates
40
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
21
53 high-level mupirocin resistant MRSA
Gene % carriagePlasmid-mediated
qacA/B 83smr 77qacH 13Chromosome-mediatednorA 96norB 98norC 93sepA 96sdrM 91mepA 91mdeA 94
Mutliple gene carriage %
qacA/B + smr 53
qacA/B + smr + qacH 11
norA + norB + norC + sep A + sdrM + mep A + mdeA
76
Overexpression %
At least 1 Chromosome-mediated efflux gene
60
norA 49
NorB 29
norC 10
mepA 6
mdeA 8
sepA 4
sdrM 4
J-Y Maillard – Teleclass, 2018
BACTERIAL RESISTANCE TO CHX IN VITROCarriage of efflux pump genes in healthcare setting isolates
41
BACTERIAL RESISTANCE TO CHX IN VITROCarriage of efflux pump genes in healthcare setting isolates
2015
J-Y Maillard – Teleclass, 2018
42
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
22
REALITY CHECK
J-Y Maillard – Teleclass, 2018
43
Microorganisms MIC mg/LBacillus spp 1 - 3Clostridium spp 1.8 - 70Corynebacterium spp 5 - 10Staphylococcus spp 0.5 - 6Streptococcus faecalis 2000 - 5000Streptococcus spp 0.1-7
Microorganisms MIC mg/LEscherichia coli 2.5 - 7.5
Klebsiella spp 1.5 - 12.5
Proteus spp 3 - 100
Pseudomonas spp 3 - 60
Serratia marcescens 3 - 75
Salmonella spp 1.6 - 5
Microorganisms MIC mg/LAspergillus spp 75 - 500
Candida albicans 7 - 15
Microsporum spp 12 - 18
Penicillium spp 150 - 200
Saccharomyces spp 50 - 125
Trichophyton spp 2.5 - 14
REALITY CHECK
J-Y Maillard – Teleclass, 2018
CHX concentrations and applications
44
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
23
Microorganisms MIC mg/LBacillus spp 1 - 3Clostridium spp 1.8 - 70Corynebacterium spp 5 - 10Staphylococcus spp 0.5 - 6Streptococcus faecalis 2000 - 5000Streptococcus spp 0.1-7
Microorganisms MIC mg/LEscherichia coli 2.5 - 7.5
Klebsiella spp 1.5 - 12.5
Proteus spp 3 - 100
Pseudomonas spp 3 - 60
Serratia marcescens 3 - 75
Salmonella spp 1.6 - 5
Microorganisms MIC mg/LAspergillus spp 75 - 500
Candida albicans 7 - 15
Microsporum spp 12 - 18
Penicillium spp 150 - 200
Saccharomyces spp 50 - 125
Trichophyton spp 2.5 - 14
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Applications Concentration (mg/L)
Eye drop 20 - 60
Skin disinfection 5,000
Surgical scrub 20,000 - 40,000
Irrigation 150 -500
Topical cream 1,000
Wash cloth 2,000
CHX concentrations and applications
45
Factors inherent to the product• concentration• formulation• water activity• pH
CONCENTRATION EXPONENT = 2
PRECIPITATION
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Factors affecting CHX efficacy
46
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
24
Factors inherent to the product• concentration• formulation• water activity• pH
REALITY CHECK
J-Y Maillard – Teleclass, 2018
INCOMPATIBILITIES• Anionic and non-ionic surfactants• Viscous materials such as acacia, sodium
alginate, sodium carboxymethylcellulose, starch, and tragacanth
• Brilliant green, chloramphenicol, copper sulfate, fluorescein sodium, formaldehyde, silver nitrate, and zinc sulfate.
• Cork (container)
PRECIPITATIONIn the presence of inorganic acids,certain organic acids, and salts, hard water
Solubility increases with cetrimide
Factors affecting CHX efficacy
47
Factors inherent to the product• concentration• formulation• water activity• pH
Factors inherent to the application• surface• organic load (soiling)• temperature• contact time• humidity
REALITY CHECKFactors affecting CHX efficacy
J-Y Maillard – Teleclass, 2018
Factors affecting CHX efficacy
48
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
25
Factors inherent to the product• concentration• formulation• water activity• pH
Factors inherent to the application• surface• organic load (soiling)• temperature• contact time• humidity
Factors inherent to the use of the product• Actual exposition time• Residual concentration• Frequency of applications• Dilution during application• Formulation delivery
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Factors affecting CHX efficacy
49
Factors inherent to the product• concentration• formulation• water activity• pH
Factors inherent to the application• surface• organic load (soiling)• temperature• contact time• humidity
Factors inherent to the use of the product• Actual exposition time• Residual concentration• Frequency of applications• Dilution during application• Formulation delivery
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Factors affecting CHX efficacy
50
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
26
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Predicting resistance and cross-resistance
51
NO
NO
Antibiotic susceptibility testing
MIC/MBC testing
Knapp et al. Appl Environ Microbiol 2015; 81(8):2652-9.
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Predicting resistance and cross-resistance
No emerging resistanceNo cross resistance
No Risk
52
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
27
NO
No emerging resistanceNo cross resistance
No Risk
YESNO Antibiotic susceptibility testing
MIC/MBC testing
YES NO
YES
Antibiotic susceptibility testing
Phenotype stability testing
No cross-resistance to antibiotics
Knapp et al. Appl Environ Microbiol 2015; 81(8):2652-9.
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Predicting resistance and cross-resistance
53
NO
Resistance likelyHigh Risk
No emerging resistanceNo cross resistance
No Risk
YESNO Antibiotic susceptibility testing
MIC/MBC testing
YES NO
YES
Antibiotic susceptibility testing
Phenotype stability testing
No cross-resistance to antibiotics
YES
Knapp et al. Appl Environ Microbiol 2015; 81(8):2652-9.
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Predicting resistance and cross-resistance
54
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
28
Transient resistancePossible Risk
NO
Resistance likelyHigh Risk
No emerging resistanceNo cross resistance
No Risk
YES
NO
NO
No established resistanceNo Risk
NO Antibiotic susceptibility testing
MIC/MBC testing
YES NO
YES
Antibiotic susceptibility testing
Phenotype stability testing
No cross-resistance to antibiotics
YES
YES
Selecting for/ maintenance of resistance High Risk
Residual activity on application (maintenance of selective pressure)
Knapp et al. Appl Environ Microbiol 2015; 81(8):2652-9.
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Predicting resistance and cross-resistance
55
Transient resistancePossible Risk
YES
NO
NO
No established resistanceNo Risk
MIC/MBC testing
NO
Antibiotic susceptibility testing
Phenotype stability testing
No cross-resistance to antibiotics`
YES
Selecting for/ maintenance of resistance High Risk
Residual activity on application (maintenance of selective pressure)
Bacterial resistance to biocides - Salmonella
enterica exposure to CHG and BZC
Knapp et al. Appl Environ Microbiol 2015; 81(8):2652-9.
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Predicting resistance and cross-resistance
56
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
29
NO
No emerging resistanceNo cross resistance
No Risk
NO Antibiotic susceptibility testing
MIC/MBC testing
Imipenem (10 μg)Ceftazidime (30 μg)Meropenem (15 μg)Tobramycin (10 μg)Aztreonam (30 μg)Bacterial resistance to biocides
Ps. aeruginosa exposure to a mouthwash 0.0000125% chlorhexidine (1/40 in use dilution)
Ps. aeruginosa exposure to a shampoo 0.000015% benzalkonium chloride (1/100 in use
dilution)
Knapp et al. Appl Environ Microbiol 2015; 81(8):2652-9.
REALITY CHECK
J-Y Maillard – Teleclass, 2018
Predicting resistance and cross-resistance
57
CONCLUSIONS
J-Y Maillard – Teleclass, 2018
58
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
30
A DEAD BUG CANNOT BECOME RESISTANT
J-Y Maillard – Teleclass, 2018
CONCLUSIONSThe obvious?
59
BIOCIDAL PRODUCT
CLP classification
TOXICITY
Efficacity:Broad spectrum
Other performances
(cleaning)
Organoleptic properties
Stability
J-Y Maillard – Teleclass, 2018
CONCLUSIONSThe obvious? Complex formulations
60
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
31
40%Median hand hygiene compliance from 95
studies.
Erasmus et al. Infect Control Hosp Epidemiol 2010;31:283-94.
J-Y Maillard – Teleclass, 2018
CONCLUSIONSThe obvious?
OVERUSEvs.
61
Improving practices (product usage) and product efficacy are essential for a better control Otter et al. ICHE 2011;32:687-99
Rutala & Weber. J Hosp Infect 2001;48:S64-8.Boyce. J Hops Infect 2007;65:50-4.
Factors affectingefficacy
Product efficacy
Product usage
Compliance
J-Y Maillard – Teleclass, 2018
CONCLUSIONSThe obvious – product usage
62
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
32
THANK YOU
Email: maillardJ@cardiff.ac.uk
J-Y Maillard – Teleclass, 2018
63
ChlorhexidineUseandBacterialResistanceProf.Jean-YvesMaillard, Cardiff University, Wales
AWebberTrainingTeleclass
HostedbyDr.LynneSehulsterwww.webbertraining.com
33
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